1. Field of the Invention
This invention provides monocyclic, thieno, pyrido, and pyrrolo pyrimidine compounds and methods of use and manufacture of the same.
2. Description of the Background Art
Pneumocystis jirovecii pneumonia formerly identified as Pneumocystis carinii pneumonia (PCP) is the most common life-threatening opportunistic infection in immuno-deficient patients with AIDS, some types of cancers or undergoing organ transplant procedures. With the advent of highly active antiretroviral therapy (HAART), PCP rates have been reduced significantly. Unfortunately, it still remains a serious infection in 30-40% of immunocompromised patients if their CD4 cell count drops below 50. While classified as a fungus, Pneumocystis jirovecii (pj), does not respond to antifungal treatments. The recommended therapeutic approach for the treatment PCP is trimethoprim (TMP)-sulfamethoxazole (SMX), but due to sulfonamide allergies and increasing drug-resistant strains, in many cases use of TMP-SMX is not recommended. The second line treatment involves potent, but non-selective DHFR inhibitors such as trimetrexate (TMQ) and piritrexim (PTX) which cause myelosuppression and require co-administration of leucovorin increasing the cost of therapy. There is a significant unmet clinical need for new anti-infective agents as reported by the Centers of Disease Control and Prevention and World Health Organization to overcome the threat of drug-resistant strains. The present invention discloses a series of 6-substituted pyrido[3,2-d]pyrimidines that are selective and potent inhibitors of pjDHFR. The synthesis and biological evaluation of analogs designed to optimize selectivity and potency for pjDHFR over hDHFR is disclosed.